The clinical implications of hypertension stem from multi-system end- organ damage. Among the most significant complications of hypertension is cardiac hypertrophy. The renin-angiotensin system has been implicated both in compensatory cardiac hypertrophy and in the pathogenesis of progressive myocardial dysfunction leading to heart failure. Recently a novel signaling mechanism for angiotensin II (Ang II) involving reactive oxygen species (ROS) has been identified in some cell types, yet the involve of this pathway in cardiomyocyte signaling remains relatively unexplored. Our preliminary evidence suggests that intracellular ROS increases may be critically involved in the hypertrophic program elicited by AngII in cardiomyocytes. This project is designed to address the hypothesis that renin-angiotensin system-dependent over-production of ROS is an important mechanism in the pathogenesis of pressure overload cardiac hypertrophy. We will dissect molecular mechanisms of this novel signaling cascade in cardiac hypertrophy, attempting to identify what ROS are important, exploring the role of NAD(P)H oxidase as a source of AngII-induced ROS generation, and elucidating downstream transcription factor activation. These studies using both in vitro and in vivo model systems, rely on highly selective genetic tools including 1) recombinant adenoviral vectors that encode redox modulating enzymes and dominant- negative inhibitors, and 2) genetically manipulated mouse strains. Our ultimate goal is to develop new therapeutic targets capable of interrupting the evolution from hypertension to hypertrophy to heart failure.